Abstract 3458: Novel anti-NME7antibody inhibits metastasis of solid tumor cancers
Authors: Cynthia Carol Bamdad, Benoit J. Smagghe, Mark G. Carter, Trevor J. Grant, Danica M. Page, Laura M. Reale, Michael J. Nash, Jac-Leen S. Nash, Andrew K. Stewart
Journal: Cancer Research (2022)

Abstract Purpose: To develop an antibody therapeutic that disrupts interaction between onco-embryonic growth factor NME7AB and its cognate growth factor receptor, MUC1*, for the treatment of solid tumors and inhibition of their metastases. Normally, NME7 is only expressed and secreted by cells of a Day 3 to Day 5 human blastocyst. NME7 expression is then turned off and expression of self-regulating, adult forms of NME proteins is turned on. However, we found that NME7 expression is mistakenly turned on again in cancer cells. Cleavage of NME7 to NME7AB enables secretion from the cell, where it then binds to and dimerizes the MUC1* extracellular domain, which activates the MAP kinase signaling cascade. Methods: Because NME7AB shares homology to other adult forms of NME proteins, which are required for normal cellular function, we needed to develop a monoclonal antibody that binds to NME7AB, but not to other NME proteins, and disrupts its interaction with the MUC1* growth factor receptor as well. To investigate the effects of NME7AB on cancer growth and metastasis, we generated populations of cancer cells that had been cultured in a serum-free media to which was added a recombinant NME7AB. The parent cells, the NME7AB grown progeny, or mixed populations were implanted into NSG mice to test the effect of novel anti-NME7AB antibodies on tumor growth and metastasis. Parent tumor cells and the NME7AB-grown cells were engineered to emit light at different wavelengths so that growth of each population could be separately tracked in live animals. Results: Cancer cells that were cultured in a serum-free media containing recombinant NME7AB for 10 days acquired characteristics of more metastatic cells, often called cancer stem cells (referred to here as NME7AB-CSCs). They upregulated metastatic markers by up to 100-fold, became non-adherent, entered dormancy and formed tumors from injection of as few as 10,000 cells. The addition of an anti-NME7AB antibody during the 10-day culture period blocked this transition. NME7AB-CSCs that were injected into the tail vein of NSG mice induced widespread metastasis in 6-10 days, after which an anti-NME7AB antibody was i.v. administered. The anti-NME7AB antibody greatly reduced or cleared the metastasis. Animals implanted sub-cutaneously with NME7AB-CSCs, then administered anti-NME7AB antibody, showed a significant reduction in the spread of breast cancer cells to the liver. Mixed populations of parent cells plus NME7AB-CSCs, which emitted light at different wavelengths, were implanted sub-cutaneously and allowed to become established. The percent of the implanted tumor that was NME7AB-CSCs determined the growth rate of the entire tumor. An anti-NME7AB antibody inhibited growth of the parent cells as well as the NME7AB-CSCs. Conclusion: These data support further pre-clinical development to allow for a clinical candidate to be tested in a metastatic as well as an adjuvant setting. Citation Format: Cynthia Carol Bamdad, Benoit J. Smagghe, Mark G. Carter, Trevor J. Grant, Danica M. Page, Laura M. Reale, Michael J. Nash, Jac-Leen S. Nash, Andrew K. Stewart. Novel anti-NME7antibody inhibits metastasis of solid tumor cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3458.